浅谈遗传性视网膜变性的高度异质性和治疗方法

High heterogeneity and treatment of inherited retinal degeneration

遗传性视网膜变性(IRD)是由包括核基因和线粒体基因在内的至少350个致病基因引起的一组具有高度临床异质性和遗传异质性的视网膜变性性疾病,多为单基因遗传。临床上IRD亚型超过50种,包括单纯的视网膜变性和综合征。高通量测序极大地促进了IRD相关基因和致病变异的鉴定,但是仍有相当高比例的患者(30%~40%)在遗传学上尚未找到致病的证据,可能跟环境因素修饰性基因有关。IRD复杂性在于同一个致病变异可以引起不同的临床表型,而相似的临床表型可以是不同的致病基因或变异导致。IRD发病可早可晚,眼底表现多种多样,在临床前或早期阶段眼底可以正常。通过眼底检查和眼科辅助检查可以较好地描述表型、评估病变严重程度。IRD的高度异质性对其治疗模式提出了巨大挑战。目前得到普遍共识的IRD治疗通常分为两大类:一类是基于基因的治疗,需要了解每个患者的致病基因;另一类是通用的治疗方法,如干细胞治疗、光遗传治疗。目前,我国在IRD诊断和治疗领域给予了越来越多的重视,不论是基因诊断还是基因治疗,都取得了巨大进展。可以期待现有的临床试验以及目前正在研究的治疗方法,将在未来5~10年为IRD患者带来崭新的治疗机遇。

Inherited retinal degeneration(IRD)is a group of retinal degenerative diseases with high clinical and genetic heterogeneity caused by at least 350 pathogenic genes,including nuclear and mitochondrial genes.Most of them are mono-genic.There are more than 50 clinical IRDs subtypes,including simple retinal degeneration and syndromes.High-throughput sequencing has greatly promoted the identification of IRDsrelated genes and pathogenic variants.However,there are still a large proportion of patients(30%~40%)without genetic evidence of IRDs,which may be related to environmental factors and modifier genes.The complexity of IRDs is that the same pathogenic variation can cause different clinical phenotypes,while similar clinical phenotypes can be caused by different pathogenic genes or variants.The onset of IRDs can be early or late.The fundus manifestations are varied,and the fundus can be normal in the preclinical or early stage.Fundus examination and ancillary tests can well describe the phenotype and evaluate the severity of the lesions.The high heterogeneity of IRDs poses a great challenge to their treatment.Currently,there is a general consensus on the treatment of IRDs,which is generally divided into two categories:one is gene-based therapy,which requires understanding the pathogenic genes of each patient;the other is generic therapies such as stem cell therapy and optogenetic therapy.At present,more and more attention has been paid to the diagnosis and treatment of IRDs in China,and great progress has been made in genetic diagnosis and gene therapy.It is expected that existing clinical trials and treatments currently under study will open up new therapeutic opportunities for patients with IRD in the next 5 to 10 years.